Psychoactive substance use disorder (PSUD) is a major global public health issue, impacting both mental well-being and social stability. It commonly involves substance abuse, dependence, and addiction. Schizophrenia (SCZ) is a frequent psychiatric comorbidity of PSUD. SCZ symptoms are classified into three categories: positive symptoms (e.g., hallucinations, delusions, disorganized thinking), negative symptoms (e.g., depression, anxiety), and cognitive impairment. Current clinical treatment for SCZ typically combines antipsychotics (targeting positive symptoms) with antidepressants (addressing negative symptoms). However, this approach faces challenges including prolonged treatment duration, limited efficacy, significant side effects, symptom relapse after discontinuation, and risk of drug dependence, all of which contribute to poor patient adherence. Furthermore, some patients continue to experience adverse outcomes such as social withdrawal and cognitive decline post-treatment, placing a substantial burden on their families. The requirement for months or even years of treatment makes injectable formulations poorly accepted by patients, while drug delivery is further complicated by the intestinal and blood-brain barriers.

On May 22, a collaborative study by Luo Tao's team from our institute and Professor Wang Xiaolei's team from the Institute of Translational Medicine at Nanchang University was published in Advanced Materials (IF: 29.4). The paper is titled "Intranasal Delivery of Near-Infrared and Magnetic Dual-Response Nanospheres to Rapidly Produce Antidepressant-Like and Cognitive Enhancement Effects."

Inspired by the snuff bottles historically used by the aristocracy as a mental stimulant, this study developed a near-infrared and magnetic dual-responsive brain delivery system for intranasal administration, denoted as CFs@DP. It integrates nanoscale iron supplements (CFs) with the D2 receptor antagonist domperidone (DP), effectively addressing the issue of "low efficiency". Under magnetic field assistance, CFs@DP can be efficiently delivered to the brain via nebulized intranasal administration. Through dual stimulation from near-infrared (NIR) irradiation and catecholamine-induced coordination complexation, the system releases Fe³⁺ and DP. This upregulates D1 and D2 receptors, enhances the AC/cAMP/CREB and PLC/IP3/Ca⟡⁺/CaMKII signaling pathways, and increases BDNF and p-CaMKII levels to regulate neuronal proliferation, differentiation, and synaptic plasticity. These mechanisms rapidly produce antidepressant-like and cognitive enhancement effects. The therapeutic efficacy of CFs@DP stems from upregulated dopamine receptor density, offering sustained benefits without directly inducing intense pleasure, thereby reducing the risk of drug dependence and addiction. This delivery system is characterized by convenient administration, active targeting, safety, non-toxicity, controlled release, and the ability to remodel synapses. Moreover, the cognitive enhancement effect of this system is also effective in normally fed (non-iron-deficient) mice, suggesting its potential application in improving learning and memory capacity.

Luo Tao and Professor Wang Xiaolei are the corresponding authors of this paper. Hu Jiangnan, a master's student from our institute, is the first author. This research was supported by the Nanchang University Interdisciplinary Innovation Fund Project, the Natural Science Foundation of Jiangxi Province, and the Key Research and Development Project of Jiangxi Province.

Synthesis, Delivery, and Therapeutic Mechanism of CFs@DP

(a) Synthesis pathway (b) Administration method (c) Controlled release and detoxification strategy (d) Stage I (During administration) therapeutic mechanism (e) Stage II (Post-administration) therapeutic mechanism